title: Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice.
abstract: BACKGROUND
  The reinforcing effects of cocaine are mediated by the mesolimbic dopamine system. Behavioral and neurochemical studies have shown that the cholinergic muscarinic M(4) receptor subtype plays an important role in regulation of dopaminergic neurotransmission.
  
  
  OBJECTIVE
  Here we investigated for the first time the involvement of M(4) receptors in the reinforcing effects of cocaine using chronic intravenous cocaine self-administration in extensively backcrossed M(4) receptor knockout (M(4) (-/-)) mice.
  
  
  METHODS
  We evaluated acquisition of cocaine self-administration in experimentally naïve mice. Both cocaine self-administration and food-maintained operant behavior were evaluated under fixed ratio 1 (FR 1) and progressive ratio (PR) schedules of reinforcement. In addition, cocaine-induced dopamine release and cocaine-induced hyperactivity were evaluated.
  
  
  RESULTS
  M(4) (-/-) mice earned significantly more cocaine reinforcers and reached higher breaking points than their wild-type littermates (M(4) (+/+)) at intermediate doses of cocaine under both FR 1 and PR schedules of reinforcement. Under the PR schedule, M(4) (-/-) mice exhibited significantly higher response rates at the lowest liquid food concentration. In accordance with these results, cocaine-induced dopamine efflux in the nucleus accumbens and hyperlocomotion were increased in M(4) (-/-) mice compared to M(4) (+/+) mice.
  
  
  CONCLUSIONS
  Our data suggest that M(4) receptors play an important role in regulation of the reward circuitry and may serve as a new target in the medical treatment of drug addiction.
authors.affiliation: Laboratory of Neuropsychiatry, Rigshospitalet University Hospital, Copenhagen, Denmark.
authors.forename: Lene S
authors.initials: LS
authors.lastname: Schmidt
authors.forename: Morgane
authors.initials: M
authors.lastname: Thomsen
authors.forename: Pia
authors.initials: P
authors.lastname: Weikop
authors.forename: Ditte
authors.initials: D
authors.lastname: Dencker
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.forename: David P D
authors.initials: DP
authors.lastname: Woldbye
authors.forename: Gitta
authors.initials: G
authors.lastname: Wortwein
authors.forename: Anders
authors.initials: A
authors.lastname: Fink-Jensen
mesh_terms: D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage* / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D003216:Conditioning, Operant / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D043588:Receptor, Muscarinic M4 / Q000235:genetics / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012055:Reinforcement Schedule; D012646:Self Administration
chemical_list: D043588:Receptor, Muscarinic M4; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D003042:Cocaine; D004298:Dopamine